Beyond stiffness: interfacial slippage and active cellular matrix remodelling in focal adhesion dynamics

Focal adhesion (FA) dynamics and cell migration depend sensitively on the mechanical properties of the extracellular matrix, yet substrate stiffness alone cannot account for the distinct behaviours observed on natural versus artificial materials. In this review, we synthesize experimental findings on cells interacting with collagen I matrices and viscoelastic hydrogels, and identify the key physical mechanisms that govern adhesion stability, turnover, and migratory efficiency. Collagen I substrates are characterized by structural anisotropy, spatial heterogeneity, and a broad spectrum of relaxation times, in contrast to the simplified and often isotropic response of artificial hydrogels. Based on these observations, we highlight the central role of interfacial slippage at the FA-substrate biointerface enabled by matrix remodelling and multi-timescale viscoelastic dissipation. We further discuss how cell-generated forces can induce collagen reorganization and surface tension gradients, potentially driving Marangoni-like flows that contribute to dynamic matrix redistribution. These processes collectively maintain adhesions in a state between stabilization and turnover, favourable for persistent migration. Finally, we consider the interplay between these mechanical mechanisms and mechanosensitive signalling, particularly involving Piezo1 ion channels. This perspective emphasizes that effective cell-matrix coupling arises from the ability of the substrate to dissipate and reorganize distribution of mechanical energy, rather than from stiffness alone.